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Towards interferon-free treatment for all HCV genotypes (gt4) - Editorial
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The Lancet June 20 2015
Heiner Wedemeyer
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany
It is surely unique in modern medicine that regulatory agencies should approve seven new compounds to treat a specific disease within just 12 months. The European Commission granted marketing authorisation for sofosbuvir, a nucleotide hepatitis C virus (HCV) polymerase inhibitor, in January, 2014. Since then, the HCV protease inhibitor simeprevir (May, 2014), the NS5A inhibitor daclatasvir (August, 2014), and the single-tablet combination of the HCV NS5 inhibitor ledipasvir with sofosbuvir (November, 2014) have reached the market; followed most recently by the three-drug combination of ombitasvir (NS5A inhibitor), the ritonavir-boosted protease inhibitor paritaprevir, and the first non-nucleosidic polymerase inhibitor dasabuvir (January, 2015). Approval of these compounds was supported by phase 2 and phase 3 trial data, presented in more than 30 original papers. Almost every study described sustained virological response rates, meaning cure of HCV infection, of 90-100%. Most importantly, the new treatments allow interferon-free therapies for a broad pool of patients who could potentially benefit from these novel drugs.1 So far, so good. But are all issues in HCV infection solved?
On closer inspection, some problems are evident. Many doctors treating HCV are realising that not every patient can be cured immediately with the new drugs. Several areas of uncertainty are emerging, including reduced efficacy of treatments in advanced cirrhosis, optimum duration of distinct combination therapies, drug-drug interactions, the role of treatment-induced or naturally occurring resistant HCV variants, the need for ribavirin, and, very importantly, drug efficacy beyond HCV genotype 1.2 Many compounds against HCV were developed by testing against HCV genotype 1-based in-vitro replication systems,3 and therefore show little efficacy against other HCV genotypes. Subsequently, all new direct-acting antivirals have been approved by the European Medicines Agency (EMA) and the US Food and Drug Administration for treatment of HCV genotype 1 infection, whereas only sofosbuvir and daclatasvir can theoretically be used for all seven HCV genotypes, frequently in the absence of clinical trial data. Even though HCV genotype 1 is the most prevalent genotype worldwide, more than 50% of anti-HCV-positive patients are infected with HCV genotypes 2-7.4, 5 Moreover, emerging data show that HCV genotype 1 infection could take a more benign clinical course than other HCV genotypes, with lower rates of progression to liver cirrhosis and reduced incidence of hepatocellular carcinoma.6, 7 Thus, data on efficacy of HCV drugs against non-1 HCV genotypes is urgently needed. HCV genotype 4 accounts for 10-15% of HCV infections worldwide and represents a particular problem in north Africa. Few data for interferon-free therapies against chronic hepatitis C due to genotype 4 are available.8 Christophe Hezode and colleagues' study9 published in The Lancet is therefore of special interest. The authors investigated the single tablet formulation of ombitasvir plus paritaprevir plus ritonavir, a combination of an HCV NS5A inhibitor with a ritonavir-boosted HCV protease inhibitor. Of note and in contrast to HCV genotype 1, the regimen is used without coadministration of dasabuvir, which is effective only against HCV genotype 1. Overall, 135 patients with HCV genotype 4 infection were studied, including 86 treatment-naive patients and 49 individuals who were not cured of HCV by a previous course of pegylated interferon alfa plus ribavirin.
Patients were treated for 12 weeks, and half of the treatment-naive and all treatment-experienced patients received ribavirin in addition. Remarkably, all but four patients had a documented sustained virological response 12 weeks after the end of therapy (100% [42/42, 95% CI 91·6-100] with the ribavirin-containing regimen, and 90·9% [40/44, 78·3-97·5] with the ribavirin-free regimen). Only three patients with virological failures occurred in the ribavirin-free group, and all of them selected distinct resistance-associated variants in the HCV NS3 and NS5A regions. Thus, so far, this trial is the largest to investigate an interferon-free regimen in HCV genotype 4 infection and show that once-daily therapy for 12 weeks with ombitasvir plus paritaprevir plus ritonavir is highly effective. On the basis of this phase 2 study, the treatment has been approved by the EMA for treatment of chronic HCV genotype 4 infection.
Several issues need to be considered, however. Most importantly, the study included only non-cirrhotic patients. Thus, there is no information about the efficacy of ombitasvir plus paritaprevir plus ritonavir in patients with HCV genotype 4-associated liver cirrhosis. Cirrhosis is well known to be associated with reduced response rates in HCV genotype 1 and 3 infection.2 The optimum treatment for genotype 4 cirrhosis remains to be determined, and in my view ombitasvir plus paritaprevir plus ritonavir with ribavirin for 12 weeks can currently be recommended only for patients without liver cirrhosis. Moreover, whether ombitasvir plus paritaprevir plus ritonavir is similarly effective across all genotype 4 subtypes is unknown.
Genotype 4 is very heterogeneous, but Hezode and colleagues' trial9 included mainly patients with genotypes 4a and 4d only. Of note, all three patients with virological failure had genotype 4d, and one might ask whether extended therapy beyond 12 weeks could have prevented relapse. Additionally, we do not know whether ombitasvir plus paritaprevir plus ritonavir would be of benefit if NS5A-resistant variants were present before therapy. Unfortunately, information about the baseline frequency of resistance-associated variants, for HCV genotype 4 or genotype 1, is not provided for trials including paritaprevir and ombitasvir. Finally, the role of ribavirin with ombitasvir plus paritaprevir plus ritonavir as treatment for HCV genotype 4 requires further investigation.
Is ribavirin also needed for previous treatment failures? Is ribavirin required in genotype 4a? What is the optimum dose of ribavirin, because lower doses associated with fewer side-effects might be sufficient?
What should interferon-free treatments for HCV genotype look like considering the currently available data? Ombitasvir plus paritaprevir plus ritonavir with ribavirin for 12 weeks is certainly a very reasonable treatment option for non-cirrhotic patients. Boosting of ritonavir requires careful assessment of comedications, which is of major relevance because 75% of European patients with hepatitis C receive other drugs, and more than a quarter of patients take more than four additional drugs.10 Sofosbuvir with ribavirin is also effective, but 24 weeks of treatment are needed based on a recent study.8 The European labels also allow a combination of simeprevir plus sofosbuvir in cirrhotic patients, but in the absence of supporting data from controlled trials. More data for ombitasvir plus paritaprevir plus ritonavir plus ribavirin, ledipasvir plus sofosbuvir (NCT02081079, completed; NCT02073656, ongoing), and daclatasvir plus sofosbuvir (NCT02032888, completed; NCT02032875, ongoing; NCT02097966, data to be presented in April, 2015 at the International Liver Congress) will become available very soon. Several additional drugs from different classes are in advanced clinical development, which could further expand treatment options in the coming years.
Highly effective interferon-free therapies are now becoming available for patients infected with HCV genotypes other than genotype 1. The next step must be to fill the gaps in the HCV disease burden worldwide11 and to ensure access to these novel therapies. HCV kills patients, but can be a curable and reversible liver disease. The drugs to eliminate HCV are now available, but only increasing treatment uptake will reduce HCV-associated morbidity and mortality.12
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